DESCRIPTION: (adapted from the abstract) Previous studies have shown that inherited abnormalities in renal hemodynamic responses to angiotensin II (AII) and sodium loading comprise a large subset of patients with essential hypertension (HTN). Independent data suggest that a genetic predisposition to HTN is a major risk factor for the development of nephropathy in insulin-dependent diabetic (IDDM) patients. Dr. Simonson suggests that alterations in renal hemodynamics and sodium handling during uncontrolled diabetes, compounded by abnormal renal responses to AII in patients genetically at risk to HTN, result in intraglomerular HTN and, ultimately, in diabetic nephropathy. These defects in glomerular filtration rate, renal blood flow, and sodium excretion may be further exacerbated by abnormal prostaglandin (PG) synthesis and excretion in IDDM. The following studies are proposed to test this hypothesis. Patients with IDDM of short duration will be studied to examine whether those individuals with a genetic predisposition to HTN as evidenced by a high Vmax of RBC Na:Li countertransport (CTT) and a family history of HTN are the same individuals who display abnormalities in renal blood flow and altered renal responsiveness to AII. PG excretion before and after AII will also be examined in the context of the patient's predisposition to HTN and hemodynamic responses to AII. The ability of angiotensin converting enzyme inhibition to correct these defects will be assessed. In the same patients, defects in the ability to achieve volume and sodium homeostasis during exogenous mineralocorticoid administration will be examined. It is anticipated that those individuals with abnormal renal hemodynamics and a genetic predisposition to HTN will fail to "escape" normally from the sodium retaining effects of mineralocorticoid administration while they are in poor glycemic control. The ability of short-term (7 day) and long-term (3 month)intensive glycemic control to correct these defects in renal hemodynamics and extracellular volume regulation will be examined. It is expected that better metabolic control will partially, but not completely, correct these defects in the patients generically predisposed to HTN. These studies of volume regulation and renal hemodynamics should provide important insights into the interaction between the genetic factors and acquired metabolic abnormalities in the pathogenesis of HTN and nephropathy in IDDM.